Environmental exposures to polychlorinated biphenyls (PCBs) are known in humans as well as lab animals to cause immunosuppression, thyroid disease, endocrine disruption, and damage to the central nervous system. Not all humans or laboratory animals respond similarly to the same dose -indicating interindividual genetic differences. In rodents to elicit these pathologies, planar PCBs must bind to, and activate, the aryl hydrocarbon receptor (AHR). Despite this overriding role for planar-PCB-mediated AHR activation in toxicity, the AHR up-regulates CYP1A2, which in liver sequesters and protects distant tissues against planar PCBs. Both the AHR and CYP1A2 are polymorphic in humans: the AHR exhibits >12-fold differences in ligand-binding affinity;liver basal CYP1A2 shows >60-fold differences in subjects having no known exposure to inducers. With regard to fetal exposure, our studies in mice demonstrate that risk of birth defects by planar TCDD depends on the high-affinity AHR and is also greatly increased in fetuses carried by dams that lack CYP1A2. PCBs represent mixtures having many dozens of different congeners;which congener is toxic, and the rates of uptake, metabolism and excretion are difficult to determine in humans, and most studies in lab animals look at a single congener. We have studied mice with the high- (Ahrb, B6) vs low- (B6.D2-Ahrd) affinity AHR, and with or without the Cyp1a2 gene. Using these mice, we hypothesize that Ahrb fetuses carried by Cyp1a2(-/-) dams will be most susceptible, and Ahrd fetuses carried by Cyp1a2(+/+) dams most resistant, to deficits in learning, memory, and other behaviors caused by planar PCBs. For the funding period, we propose to: [1] determine tissue distribution of each of eight PCB congeners (most relevant to humans) given as a mixture -comparing B6 vs B6.D2-Ahrd, and Cyp1a2(+/+) vs Cyp1a2(-/-) dams and their offspring;and [2] evaluate the in utero and lactational effects of this orally administered PCB mixture on learning, memory, and other behaviors in offspring of these treated dams, starting at postnatal day 60. These studies will define the impact of a fetal basis for adult disease. The Ahr and Cyp1a2 genotypes in these mice represent the extremes for variability of these two genes in the human population. There exist genetic differences in mouse (and human) populations, which represent a gradient of at-risk individuals. Project Narrative: Polychlorinated biphenyls (PCBs) are widespread persistent organic pollutants linked to numerous human health problems, including learning and memory deficits in children of exposed mothers. The Ahr and Cyp1a2 genotypes in our mouse models represent the extremes for variability in these two genes in the human population, and both genes likely play a role in susceptibility following PCB exposure. These studies will define the fetal basis for adult disease and help to identify individuals at greatest risk of PCB-induced neurotoxicity.